1. Home>
2. Specialty Care>
3. HIV/AIDS>
4. Feature

Antiretroviral Failure: A Biopsychosocial Approach

Behavioral issues, through their effect on adherence, often lie at the root of antiretroviral failure. If not addressed, these issues are likely to jeopardize the success of any future treatment.

How to manage patients who have failed one or more intensive antiretroviral regimens is one of the most vexing questions in the current treatment of HIV. An increasingly common scenario involves a patient who may have initially responded favorably to antiretroviral therapy, but whose viral load is now increasing. Such a patient may have been exposed to numerous antiretroviral drugs in a succession of combination regimens. In these scenarios, consultants are often asked to help design salvage regimens.

When a patient's antiretroviral therapy is identified as "failing," the natural impulse is to seek another regimen that will succeed. The desire to fully suppress viral replication, however, must be tempered by a full appreciation of the implications of changing therapy. The clinician should consider two factors. First, the overall success rates of salvage regimens are significantly lower than the success rates of initial therapies, probably for two reasons: (a) cross-resistance between agents used in the salvage regimen and agents used in previous failing regimens and (b) reduced adherence to salvage regimens caused by increased complexity, pill burden, and toxicity. Second, if a salvage regimen is not fully suppressive or is not taken correctly, it may lead to the selection of additional resistance mutations, making the patient's virus even more difficult to treat in the future. Every change in therapy, therefore, carries significant risks. Such changes should generally be undertaken with reluctance and only when the anticipated benefits clearly outweigh these risks.

Unfortunately, no clear definition of treatment failure is available to guide clinicians in changing therapy. Table 1 lists some of the many definitions of treatment failure currently in use among HIV clinicians. Depending on the definitions chosen (and the sensitivity of the viral-load assay used), many patients are virologic failures but remain immunologic and clinical successes. Although there is good evidence that lower viral loads are associated with longer duration of viral suppression, the relation is not invariable. Indeed, some patients experience a rising viral load without immunologic or clinical deterioration, and such discordances remain poorly understood. Moreover, there is no consensus on which specific viral-load levels or other indicators signify the need for a change in therapy.

The ongoing controversy in this area should not be surprising. The success or failure of antiretroviral therapy is not a purely biologic phenomenon, but is rather the product of a complex interaction between biologic and behavioral factors. Behavioral issues, through their effect on adherence, often lie at the root of antiretroviral failure. If not addressed, these issues are likely to jeopardize the success of any future treatment. Because adherence is so important and so variable, decisions regarding initiation or change of therapy cannot be based solely on biologic factors, and clear biologic cut-points for medication changes are likely to remain elusive. As long as adherence remains critical to the success of antiretroviral therapy, the phenomenon of treatment failure will need to be analyzed in an expansive biopsychosocial context involving the virus, the patient, and the clinician.

Viral Factors

Increasingly, patients are arriving in clinicians' offices with viruses that are already resistant to one or more medications. These patients either acquired resistant viruses at transmission or, more likely, developed resistant strains during previous antiretroviral treatment. Clinicians need to make a careful assessment of the patient's viral resistance before initiating treatment. A careful history of prior antiretroviral therapy is essential in this regard. Genotypic and phenotypic resistance assays are increasingly important tools, at least in some patients. These assays may be easier to interpret in treatment-naive than in treatment-experienced patients, who are likely to carry an archive of viral subspecies with a variety of resistance patterns. Resistance assays are likely to detect only those subspecies resistant to current therapy, and archived subspecies may "fly below the radar" of the current tests. In treatment-experienced patients, resistance assays should be performed while they are on treatment or within 2 weeks of stopping treatment, because wild-type virus will quickly become the majority species once antiretrovirals are stopped. Until resistance assays become far more sensitive, a meticulous history of prior antiretroviral therapy (see below) will continue to be indispensable.

Patient Factors

Antiretroviral therapy demands enormous commitment and discipline from patients. Although some highly motivated patients can adhere rigorously to their therapies, most patients are not always 100% adherent. Adherence failure is probably the single greatest contributor to treatment failure. Common causes of adherence lapses include inadequate education and preparation before starting therapy, drug toxicities, interruptions in the supply of medications (such as temporary Medicaid denials), substance misuse, depression, and family crises (such as serious illnesses, deaths, and housing problems). Before starting therapy, and frequently thereafter, patients should be instructed that if they are unable to continue all their medications, they should stop all drugs simultaneously and then resume all drugs simultaneously once the obstacle to adherence has been resolved. This will minimize the likelihood of developing resistance. Even when this message is carefully conveyed during patient education, not all patients recall or apply it.

For some patients, even keeping clinic appointments is a major challenge. In one study, missed appointments were the only independent predictor of antiretroviral failure. Anecdotal evidence suggests that the lack of a consistent relationship with a primary-care provider also bodes poorly for success of antiretroviral therapy. Patients who "shop" from clinician to clinician, who frequently walk in for medication refills without appointments, and who do not undergo blood tests on a regular basis appear to have increased rates of antiretroviral failure. Patients who relate to care in such ways might do better interrupting or delaying their antiretroviral treatment until they can establish a more consistent relationship with a clinician.

Clinician Factors

When a patient's antiretroviral therapy fails, some of the responsibility may fall on the practitioner. Indeed, a clinician's first responsibility is to select patients wisely for antiretroviral treatment. Not all HIV-positive patients require antiretroviral therapy. Based on a patient's CD4-cell count and viral load, it is possible to assess the patient's likelihood of progressing to AIDS in the near future. Even when a patient meets the usual guidelines for starting antiretroviral therapy, treatment might best be postponed until that patient's prospects for adherence are maximized. Initiation of antiretroviral therapy is rarely an emergency. Time can almost always be found to lay a solid foundation for a primary-care relationship, assess the patient's lifestyle, and assure oneself that the patient has a reasonable chance of adhering to a complex regimen. Patients diagnosed with HIV during hospitalization, as well as those with a history of inconsistent behavior in the outpatient setting, should be supported in forming a stable bond with an outpatient care provider before antiretroviral therapy is started. Patients with active substance-abuse problems, active psychiatric illness, and severe personal or family stressors need not be denied antiretroviral therapy, but extra care should be taken to assess and stabilize such challenges before medication is initiated.

Clinicians greatly affect the likelihood of antiretroviral success through the regimens they recommend. In choosing a regimen, both biology and behavior must be carefully considered. A thorough treatment history must be compiled for pretreated patients, regardless of whether resistance assays are used. This history should include medications and combinations used, doses prescribed and taken, duration of each regimen, level of adherence to each drug in each combination, drug toxicities experienced, and reasons for each change. If the patient cannot reliably provide this level of detail, a review of medical records may be necessary.

Selecting a regimen depends not only on viral sensitivity, but also on the patient's lifestyle. Before recommending a regimen, the clinician should inquire about the patient's daily activities, with attention to such issues as sleeping and mealtime schedules, travel habits, medication storage, privacy needs, and substance use. Differences between weekday and weekend schedules should be considered. The patient's medication regimen should be tailored to fit these daily schedules, rather than presented in generic BID or TID formats. The clinician should identify any prescription drugs that might interact with antiretrovirals.

Although many primary care providers are skilled in the routine management of patients on antiretroviral therapy, not all are fully versed in the intricacies of the growing array of HIV drugs. After collecting the above data, many primary-care clinicians will find it prudent to consult with a more experienced colleague before initiating therapy, and most should consider a consultation before changing an existing regimen.

Selecting an antiretroviral regimen should ideally be a negotiation between clinician and patient. Before dispensing prescriptions, the timing and content of each medication session should be written out on a schedule that includes the patient's other regular daily activities. The patient should have an opportunity to evaluate the proposed schedule. For example, if the patient feels that a lunchtime dose is impractical, the clinician may need to redesign the regimen to eliminate mid-day doses.

Finally, clinicians can contribute to the success of antiretroviral therapy through assiduous and continuous attention to adherence issues. Patients must be educated in the essentials of their particular regimen, the requirement for near-perfect adherence, and the need to completely interrupt therapy rather than take partial therapy. The clinician should instill this information in depth before medication is started or changed and should reinforce the message in part or in whole at each follow-up visit. Suggestions of ways to enhance patients' adherence are listed in Table 2. It is difficult to objectively measure medication adherence, and clinicians' subjective assessments of adherence are notoriously poor. However, Table 3 contains some questions that may be useful in this regard. When taking an adherence history, do not ask leading questions that elicit answers patients think the clinician wants to hear. Encourage patients to describe their regimens and their adherence patterns in their own words and facilitate their disclosure of adherence "lapses."

Assessing "Treatment Failure"

When the viral load starts to rise, the clinician should remember all of the complex factors that contribute to the success or failure of antiretroviral therapy. Before changing to a salvage regimen, the clinician should look for an explanation for the apparent failure.

First, keep in mind that an elevated viral load while on therapy is not necessarily a sign of drug resistance. A viral load may be falsely elevated because of an immunization or intercurrent illness at, or shortly before, the time of the assay. Patients may not remember these events when they return to the clinic after a high viral load. It is almost always a good idea to repeat the assay at a "safe" time before exploring changes in therapy. Viral loads may also be falsely elevated because of an interruption in treatment. A total or a brief partial interruption may not have led to the evolution of resistant virus (see Research Notes in this issue of ACC). A careful adherence history may suggest that the patient's virus is still likely to be sensitive to the initial therapy.

If the history suggests anything less than perfect adherence, particularly at the time of the viral-load assay, the clinician should attempt to optimize adherence by addressing the problems identified in the history. Again, it may be useful to interrupt therapy entirely until the patient's life circumstances have stabilized and adherence can be maximized. After the patient has made the best possible effort to adhere to the current therapy for 4 weeks, the viral load can be rechecked. If the viral load has declined significantly, the old regimen may be continued, and the viral load rechecked after another 6 to 8 weeks. If the viral load remains high despite the best possible adherence to current therapy, the patient's therapeutic prospects should be assessed based on his or her CD4-cell count, viral load, and adherence history. In some cases, continuing the old regimen despite an imperfect virologic response may be the best course. This is particularly true when the viral load on the old regimen is significantly lower (at least 1 to 2 log10) than the patient's baseline and the prospects for greater biologic and behavioral success on a new regimen seem poor. Before the regimen is changed, consider using a resistance assay to confirm the virus's genotypic and/or phenotypic response to each drug in the combination. An interruption in therapy, with careful monitoring of the CD4-cell count, may be appropriate while a new regimen is designed. Researchers are actively studying this strategy. As always, both psychosocial and biologic factors should be considered in designing the new treatment plan, and consultation with an antiretroviral expert may be useful.

Conclusions

Successful antiretroviral therapy requires not only carefully chosen medications, but also careful selection of patients who are ready and able to begin or continue treatment, a solid relationship between patient and clinician, and clinician expertise and commitment to adherence support. If adherence is in doubt, deferral or interruption of therapy may be preferable to initiation or continuation of treatment. Because of problems with cross-resistance and adherence, changes in therapy are inherently risky. When antiretroviral therapy appears to be failing, explanations other than viral resistance should be carefully explored, and patients and clinicians should work aggressively to optimize adherence to current therapy before changing to a salvage regimen.

— Bruce Soloway, MD, and Gerald Friedland, MD

Dr. Soloway is an Associate Editor of ACC. Dr. Friedland is Consulting Editor of ACC.

Published in AIDS Clinical Care March 1, 2000

Citation(s):

Clumeck N. Choosing the best initial therapy for HIV-1 infection. N Engl J Med 1999 341 1925-1926.

• Original article (Subscription may be required)
• Medline abstract (Free)

Cohen, OJ. Antiretroviral therapy: Time to think strategically. Ann Intern Med 2000 132 320-322.

• Original article (Subscription may be required)
• Medline abstract (Free)

Friedland GH, et al. Attaining higher goals in HIV treatment. AIDS 1999 13 suppl 1 S61-S72.

Henry K. The case for more cautious, patient-focused antiretroviral therapy. Ann Intern Med 2000 132 306-311.

• Original article (Subscription may be required)
• Medline abstract (Free)

Ledergerber B et al. Clinical progression and virological failure on HAART in HIV-1 patients. Lancet 1999 353 863-868.

• Medline abstract (Free)

Lucas GM et al. Highly active antiretroviral therapy in a large urban clinic. Ann Intern Med 1999 131 81-87.

• Original article (Subscription may be required)
• Medline abstract (Free)